Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 769
Filtrar
1.
Twin Res Hum Genet ; 23(5): 271-277, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33190678

RESUMO

Previous genetic studies on hair morphology focused on the overall morphology of the hair using data collected by self-report or researcher observation. Here, we present the first genome-wide association study (GWAS) of a micro-level quantitative measure of hair curvature. We compare these results to GWAS results obtained using a macro-level classification of observable hair curvature performed in the same sample of twins and siblings of European descent. Observational data were collected by trained observers, while quantitative data were acquired using an Optical Fibre Diameter Analyser (OFDA). The GWAS for both the observational and quantitative measures of hair curvature resulted in genome-wide significant signals at chromosome 1q21.3 close to the trichohyalin (TCHH) gene, previously shown to harbor variants associated with straight hair morphology in Europeans. All genetic variants reaching genome-wide significance for both GWAS (quantitative measure lead single-nucleotide polymorphism [SNP] rs12130862, p = 9.5 × 10-09; observational measure lead SNP rs11803731, p = 2.1 × 10-17) were in moderate to very high linkage disequilibrium (LD) with each other (minimum r2 = .45), indicating they represent the same genetic locus. Conditional analyses confirmed the presence of only one signal associated with each measure at this locus. Results from the quantitative measures reconfirmed the accuracy of observational measures.

2.
Nat Commun ; 11(1): 5980, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239672

RESUMO

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

3.
Twin Res Hum Genet ; 23(4): 214-220, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32885774

RESUMO

Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.

4.
Commun Biol ; 3(1): 510, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934300

RESUMO

Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be reliably extracted from in-vivo MRI must be established. Using four independent test-retest datasets, we found high reliability across the brain (intraclass correlation interquartile range: 0.65-0.85). Heritability estimates were derived for three family-based cohorts using variance components analysis and pooled (total N > 3000); the overall sulcal heritability pattern was correlated to that derived for a large population cohort (N > 9000) calculated using genomic complex trait analysis. Overall, sulcal width was the most heritable metric, and earlier forming sulci showed higher heritability. The inter-hemispheric genetic correlations were high, yet select sulci showed incomplete pleiotropy, suggesting hemisphere-specific genetic influences.

5.
Twin Res Hum Genet ; 23(4): 204-213, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32755526

RESUMO

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10-10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10-6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10-3; p = 2.29 × 10-3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10-3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

6.
Sleep ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32805044

RESUMO

STUDY OBJECTIVE: Sleep is essential for both physical and mental health, and there is a growing interest in understanding how different factors shape individual variation in sleep duration, quality and patterns, or confer risk for sleep disorders. The present study aimed to identify novel inferred causal relationships between sleep-related traits and other phenotypes, using a genetics-driven hypothesis-free approach not requiring longitudinal data. METHODS: We used summary-level statistics from genome-wide association studies and the latent causal variable (LCV) method to screen the phenome and infer causal relationships between seven sleep-related traits (insomnia, daytime dozing, easiness of getting up in the morning, snoring, sleep duration, napping, and morningness) and 1,527 other phenotypes. RESULTS: We identify 84 inferred causal relationships. Among other findings, connective tissue disorders increase insomnia risk and reduce sleep duration; depression-related traits increase insomnia and daytime dozing; insomnia, napping and snoring are affected by obesity and cardiometabolic traits and diseases; and working with asbestos, thinner, or glues may increase insomnia risk, possibly through an increased risk of respiratory disease or socio-economic related factors. CONCLUSION: Overall, our results indicate that changes in sleep variables are predominantly the consequence, rather than the cause, of other underlying phenotypes and diseases. These insights could inform the design of future epidemiological and interventional studies in sleep medicine and research.

7.
Psychol Med ; : 1-10, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32744192

RESUMO

BACKGROUND: Despite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG. METHODS: Participants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates. RESULTS: Neither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality. CONCLUSIONS: These findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.

8.
J Abnorm Psychol ; 129(7): 737-747, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32816500

RESUMO

Marriage and parenthood are associated with alcohol use and use disorder (AUD), although they are confounded such that many studies struggle to identify their unique and/or causal effects. The present study utilized a genetically informed discordant twin design that strengthens the putative causal role of marital and parental status in the presentation of AUD symptoms by using each individual's cotwin as their own control while simultaneously modeling both predictors among men and women. Participants were 980 complete same-sex twin pairs from the Australian Twin Registry (Mage = 31.70 [SD = 2.48]; 71% women). Marital status, parental status, and past year AUD symptoms were assessed via semistructured interview. Three random-intercept generalized linear mixed models were fit in men and women including (a) marital status only, (b) parental status only, and (c) both marital and parental status; demographics, past year pregnancy, age of first drink, age of regular drinking, personality traits, and antisociality were included as covariates. Models tested for quasi-causal and familial effects. The sole-predictor marital status model (Model 1) provided the best fit among men, while the simultaneous-predictor marital and parental status model (Model 3) provided the best fit among women. Sole-predictor models showed familial effects of both predictors among men and quasi-causal and familial effects of both predictors among women; the simultaneous-predictor model revealed familial effects of marital status only among men and quasi-causal effects of parental status only among women. The present study elucidates important sex differences in the presentation of AUD among midlife adults in the context of notable developmental milestones. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

9.
Sci Rep ; 10(1): 12681, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728164

RESUMO

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a2 = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c2 = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a2 = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a2 = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c2 = 0.31; 0.29-0.33 and c2 = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.

10.
Hum Mol Genet ; 29(17): 2976-2985, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32716505

RESUMO

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

11.
Sci Rep ; 10(1): 12609, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724068

RESUMO

Scores on an optimistic-pessimistic personality scale have been associated with mortality, but optimism and pessimism scores are separable traits and it is unclear which has effects on health or longevity. The Life Orientation Test (LOT), containing items for optimism and pessimism, was included in a twin study on health of Australians aged over 50 in 1993-1995. After a mean of 20 years, participants were matched against death information from the Australian National Death Index. 1,068 out of 2,978 participants with useable LOT scores had died. Survival analysis tested for associations between separate optimism and pessimism scores and mortality from any cause, and from cancers, cardiovascular diseases or other known causes. Age-adjusted scores on the pessimism scale were associated with all-cause and cardiovascular mortality (Hazard Ratios per 1 standard deviation unit, 95% confidence intervals and p-values 1.134, 1.065-1.207, 8.85 × 10-5 and 1.196, 1.045-1.368, 0.0093, respectively) but not with cancer deaths. Optimism scores, which were only weakly correlated with pessimism scores (age-adjusted rank correlation = - 0.176), did not show significant associations with overall or cause-specific mortality. Reverse causation (disease causing pessimism) is unlikely because in that case both cardiovascular diseases and cancers would be expected to lead to pessimism.

12.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

13.
Sci Rep ; 10(1): 9713, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546850

RESUMO

Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability (hsnp2) estimates were ~10%, and both traits were highly genetically correlated (LDSC rg > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant.

14.
BMJ Open ; 10(5): e032580, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32461290

RESUMO

PURPOSE: Depression is the most common psychiatric disorder and the largest contributor to global disability. The Australian Genetics of Depression study was established to recruit a large cohort of individuals who have been diagnosed with depression at some point in their lifetime. The purpose of establishing this cohort is to investigate genetic and environmental risk factors for depression and response to commonly prescribed antidepressants. PARTICIPANTS: A total of 20 689 participants were recruited through the Australian Department of Human Services and a media campaign, 75% of whom were female. The average age of participants was 43 years±15 years. Participants completed an online questionnaire that consisted of a compulsory module that assessed self-reported psychiatric history, clinical depression using the Composite Interview Diagnostic Interview Short Form and experiences of using commonly prescribed antidepressants. Further voluntary modules assessed a wide range of traits of relevance to psychopathology. Participants who reported they were willing to provide a DNA sample (75%) were sent a saliva kit in the mail. FINDINGS TO DATE: 95% of participants reported being given a diagnosis of depression by a medical practitioner and 88% met the criteria for a lifetime depressive episode. 68% of the sample report having been diagnosed with another psychiatric disorder in addition to depression. In line with findings from clinical trials, only 33% of the sample report responding well to the first antidepressant they were prescribed. FUTURE PLANS: A number of analyses to investigate the genetic architecture of depression and common comorbidities will be conducted. The cohort will contribute to the global effort to identify genetic variants that increase risk to depression. Furthermore, a thorough investigation of genetic and psychosocial predictors of antidepressant response and side effects is planned.

15.
Nat Commun ; 11(1): 2611, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457298

RESUMO

Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Transtornos Relacionados ao Uso de Opioides/imunologia , Viroses/imunologia , Adulto , Antivirais/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferons/farmacologia , Leucócitos Mononucleares , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Morfina/farmacologia , Análise de Célula Única , Adulto Jovem
16.
Nat Commun ; 11(1): 1647, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242144

RESUMO

Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identify 143 independent loci in 112 1-Mb regions, providing insights into the physiology of vitamin D and implicating genes involved in lipid and lipoprotein metabolism, dermal tissue properties, and the sulphonation and glucuronidation of 25OHD. Mendelian randomization models find no robust evidence that 25OHD concentration has causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes have (direct or indirect) causal effects on 25OHD concentration, clarifying the epidemiological relationship between 25OHD status and the health outcomes examined in this study.


Assuntos
Deficiência de Vitamina D/genética , Vitamina D/análogos & derivados , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reino Unido , Vitamina D/sangue , Deficiência de Vitamina D/sangue
17.
Twin Res Hum Genet ; 23(1): 23-32, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32248883

RESUMO

Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7-73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.


Assuntos
Dislexia/genética , Fatores de Transcrição Forkhead/genética , Transtornos do Desenvolvimento da Linguagem/genética , Adulto , Idoso , Aptidão , Austrália , Axônios/metabolismo , Axônios/fisiologia , Estudos de Coortes , Feminino , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/fisiologia , Fonética , Polimorfismo de Nucleotídeo Único , Leitura , Fala
18.
Nat Genet ; 52(4): 437-447, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231276

RESUMO

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Transtorno Bipolar/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sensibilidade e Especificidade
19.
Drug Alcohol Depend ; 210: 107966, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32276208

RESUMO

BACKGROUND: Caffeine, alcohol, nicotine and cannabis are commonly used psychoactive substances. While the use of these substances has been previously shown to be genetically correlated, causality between these substance use traits remains unclear. We aimed to revisit the genetic relationships among different measures of SU using genome-wide association study (GWAS) summary statistics from the UK Biobank, International Cannabis Consortium, and GWAS & Sequencing Consortium of Alcohol and Nicotine use. METHODS: We obtained GWAS summary statistics from the aforementioned consortia for ten substance use traits including various measures of alcohol consumption, caffeine consumption, cannabis initiation and smoking behaviours. We then conducted SNP-heritability (h2) estimation for individual SU traits, followed by genetic correlation analyses and two-sample Mendelian randomisation (MR) studies between substance use trait pairs. RESULTS: SNP h2 of the ten traits ranged from 0.03 to 0.11. After multiple testing correction, 29 of the 45 trait pairs showed evidence of being genetically correlated. MR analyses revealed that most SU traits were not causally associated with each other. However, we found evidence for an MR association between regular smoking initiation and caffeine consumption 40.17 mg; 95 % CI: [24.01, 56.33] increase in caffeine intake per doubling of odds in smoking initiation). Our findings were robust against horizontal pleiotropy, SNP-outliers, and the direction of causality was consistent in all MR analyses. CONCLUSIONS: Most of the substance traits were genetically correlated but there is little evidence to establish causality apart from the relationship between smoking initiation and caffeine consumption.

20.
Neuroimage ; 212: 116691, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32126298

RESUMO

It is well established that higher cognitive ability is associated with larger brain size. However, individual variation in intelligence exists despite brain size and recent studies have shown that a simple unifactorial view of the neurobiology underpinning cognitive ability is probably unrealistic. Educational attainment (EA) is often used as a proxy for cognitive ability since it is easily measured, resulting in large sample sizes and, consequently, sufficient statistical power to detect small associations. This study investigates the association between three global (total surface area (TSA), intra-cranial volume (ICV) and average cortical thickness) and 34 regional cortical measures with educational attainment using a polygenic scoring (PGS) approach. Analyses were conducted on two independent target samples of young twin adults with neuroimaging data, from Australia (N â€‹= â€‹1097) and the USA (N â€‹= â€‹723), and found that higher EA-PGS were significantly associated with larger global brain size measures, ICV and TSA (R2 â€‹= â€‹0.006 and 0.016 respectively, p â€‹< â€‹0.001) but not average thickness. At the regional level, we identified seven cortical regions-in the frontal and temporal lobes-that showed variation in surface area and average cortical thickness over-and-above the global effect. These regions have been robustly implicated in language, memory, visual recognition and cognitive processing. Additionally, we demonstrate that these identified brain regions partly mediate the association between EA-PGS and cognitive test performance. Altogether, these findings advance our understanding of the neurobiology that underpins educational attainment and cognitive ability, providing focus points for future research.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA